Peptides are implicated in a wide variety of biochemical processes in humans and other mammals. The design of peptide mimics which are resistant to degradation by proteolytic enzymes has become of increasing interest to peptide chemists. A primary goal has been to reduce the susceptibility of mimics to cleavage and inactivation by peptidases.
Somatostatin (SRIF; somatotropin release inhibiting factor), a cyclic tetradecapeptide, was first isolated from bovine hypothalamus and characterized as an inhibitor of growth hormone secretion. SRIF receptors have been found not only on pituitary cells but also in the brain, on gastric or pancreatic cells, and elsewhere. This has stimulated interest in the isolation of SRIF receptors by affinity chromatography in amount sufficient for partial sequence determination. For example, He, et al, Proc. Natl. Acad. Sci. (USA), 1989, 86, 1480, have described the use of D-Trp.sup.8 SRIF as an affinity ligand.
The bioactive conformation of SRIF is believed to include a .beta.-turn involving residues 7-10 (Phe.sup.7 -Trp.sup.8 -Lys.sup.9 -Thr.sup.10) (SEQ ID NO:1). These four amino acids have been shown to be necessary and sufficient for receptor recognition and activation, so long as they are held in the proper orientation. Somatostatin accomplishes this proper orientation through its ten remaining amino acids and the cystine bridge contained therein. In a number of active cyclic hexapeptide analogs for somatostatin, proper orientation of the four amino acids is maintained via dipeptide segments. For example, Veber and Hirschmann, et al., Life Sciences, 1984, 34, 1371 and Nature, 1981, 292 have reported that cyclic hexapeptides typified by cyclo(Pro-Phe-D-Trp-Lys-Thr-Phe) are potent mimics of somatostatin.